title: Significance of the entire C-terminus in biological activities mediated by the RON receptor tyrosine kinase and its oncogenic variant RON160.
abstract: The RON receptor tyrosine kinase regulates epithelial cell homeostasis and tumorigenesis by transducing multiple signals through its functional domains. The present study was to determine the significance of the entire C-terminus in RON or its variant RON160-mediated activities related to cell motility and tumorigenesis. Analysis of protein phosphorylation revealed that elimination of the entire C-terminus significantly impairs the ligand-dependent or independent RON or RON160 phosphorylation and dimerization. Phosphorylation of downstream signaling proteins such as Erk1/2, AKT, and p38 MAP kinase was also diminished in cells expressing the C-terminus-free RON or RON160. These dysfunctional activities were accompanied with the inability of truncated RON or RON160 to mediate cytoplasmic beta-catenin accumulation. Functional analysis further demonstrated that truncation of the C-terminus significantly impairs RON or RON160-mediated cell proliferation, morphological changes, and cellular migration. Significantly, oncogenic RON160-mediated tumor growth in athymic nude mice was lost after the deletion of the C-terminus. Thus, the C-terminus is a critical component of the RON receptor. The entire C-terminus is required for RON or RON160-mediated intracellular signaling events leading to various cellular activities.
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, PR China. luyi_19801211@163.com
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Hang-Ping
authors.initials: HP
authors.lastname: Yao
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D051176:beta Catenin; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases